“We were pleased to find that our spider venom peptide also inhibits the PIEZO1 channel.”

Frederick Sachs, PhD, SUNY Distinguished Professor

Department of Physiology and Biophysics

BUFFALO, N.Y. – A genetic mutation that alters the
kinetics of an ion channel in red blood cells has been identified
as the cause behind a hereditary anemia, according to a
paper published this month in the Proceedings of the National
Academy of Sciences by University at Buffalo scientists and
colleagues.

The research team was led by Frederick Sachs, PhD, SUNY
Distinguished Professor in the UB Department of Physiology and
Biophysics, who discovered in the 1980s that some ion channels are
mechanosensitive, that is, they convert mechanical stress into
electrical or biochemical signals.

The findings of the new study are significant, Sachs says,
because it is the first time defects in a mechanosensitive ion
channel have been implicated as the cause of a disease.

“We found that the mutations in the gene that codes for
the ion channel called PIEZO1 causes the channel to stay open too
long, causing an ion leak in red cells,” explains Sachs.
“Calcium and sodium enter, and potassium leaves, and that
affects the ability of the red cell to regulate its volume. The
cells become dehydrated and can break open, releasing their
hemoglobin into the blood, and causing symptoms, such as the
shortness of breath seen in anemic patients.”

The anemia that results from the mutations in PIEZO1 is called
familial xerocytosis, a mild to moderate form of anemia. The
ion channel, PIEZO1, is about 10 nanometers across, and it
increases its dimensions significantly upon opening; that change in
dimensions is what is responsible for its mechanical
sensitivity.

Mechanosensitive ion channels are likely to play a role in many
diseases, since all cells are mechanically sensitive. Sachs and his
colleagues have worked on activation of these channels in Duchenne
muscular dystrophy, which is caused by errors in a gene coding for
a fibrous protein that reinforces the cell membrane. The increased
stress caused by this loss of reinforcement causes the channels to
open and the leak of calcium is likely what causes the muscles to
atrophy, Sachs explains.

Sachs and colleagues at UB founded a biotech company in Buffalo,
Tonus Therapeutics to create a therapy for muscular dystrophy based
on a peptide they discovered that inhibits the channels involved in
that disease. They originally discovered the peptide in a tarantula
venom but now it is synthesized chemically. The peptide has
received orphan drug designation from the FDA.

“This means our peptide could be a potential therapy in
blood diseases, where there are defects in the ways that red blood
cells regulate cell volume,” he says.

In normal cells, he says, the mechanosensitive ion channels
usually remain closed.

“I think the cells use them as emergency valves so the
only time they open is when cells are under extreme stress,”
he explains. “Consequently, our peptide doesn’t bother
healthy cells, so it’s nontoxic. It only affects unhealthy
cells, cells which are mechanically stressed.”

Co-authors with Sachs and Gottlieb are postdoctoral fellows
Chilman Bae, PhD and Radhakrishnan Gnanasambandam and Christopher
L. Nicolai, all in the Department of Physiology and Biophysics of
the UB School of Medicine and Biomedical Sciences.

The research was supported by the National Institutes of Health,
the U.S. Department of Defense and the Children’s Guild of
Buffalo.